Enteric viral infections, including rotaviruses and noroviruses, remain one of the greatest public health challenges worldwide. In addition, the intestinal mucosa is a critical site for early control of HIV replication and dissemination. Understanding the cellular and molecular mechanisms through which the mucosal immune system recognizes and successfully eradicates enteric viral pathogens is critical for designing better oral vaccines. However, fundamental questions remain unanswered regarding (i) where virus-specific effector and memory T cell responses are primed in the intestinal mucosa;(ii) how the innate immune system recognizes enteric viruses;and (iii) how alterations in intestinal microbiota influence anti-viral immune responses. In preliminary studies, we established mouse Norovirus (MNV) as a model of natural enteric viral infection in humans and generated new tools to track MNV-specific T cell responses. Our preliminary data support the hypothesis that intestinal epithelial cells (lECs) and intestinal commensal bacteria can promote virus-specific T cell responses and host protective immunity following MNV infection. Based on these findings, three fundamental questions will be tested in this proposal (i) Where are MNV- specific T cell responses primed and what regulates MNV-specific memory T cell responses? (ii) How do innate immune cells recognize and respond to MNV infection in the gut? (iii) How do commensal microbial communities influence innate and adaptive immunity to MNV? Collectively, these studies will interrogate the influence of the innate immune response and environmental pathways on the priming and maintenance of MNV-specific T cell responses and host protective immunity in the intestine. Understanding the mechanisms through which the mucosal immune system successfully recognizes enteric viral pathogens and mounts a protective innate and adaptive immune response will be critical for the design of a new generation of successful immuno-modulatory drugs and oral vaccines. PUBLIC HEALTH RELEVANCE: Intestinal viral infections are a major worldwide cause of gastroenteritis and diarrhea leading to significant morbidity and mortality. In addition, the intestinal mucosa is a critical site for early control of HIV replication and dissemination. However, we understand relatively little about the development anti-viral innate and adaptive immunity following enteric viral infection. This proposal will address these gaps in knowledge.